ABSTRACT There is a substantial and growing population of children/adolescents who are HIV exposed uninfected (HEU) in sub-Saharan Africa (SSA). There is emerging evidence that fetal exposure to maternal infections and medications may result in adverse adult/adolescent mental health outcomes; it is plausible that fetal exposure to HIV or antiretrovirals (ART) could similarly influence long-term outcomes. Despite evidence for poor growth and neurodevelopmental deficits, programs to systematically monitor neurodevelopmental and mental health outcomes among HEU at a population level are lacking. Understanding whether there are increased adverse neurodevelopmental and mental health outcomes in HEU due to fetal HIV/ART exposure has been challenged by difficulties in defining appropriate comparator cohorts, changing PMTCT treatment guidelines, and lack of validated, scale-able assessment tools. Our team has a unique track record for moving novel approaches for screening and testing from pilot to implementation, conducting large scale evaluations, and conducting neurodevelopmental and mental health assessments in HIV-affected children and adolescents. We propose parallel longitudinal and population based HEU/HUU cohorts, in urban and rural settings, spanning infants/children/adolescents age 6 weeks to 18 years to determine differences in neurodevelopmental and mental health outcomes. The R61 phase will accrue a longitudinal homogenous cohort of 2000 HEU/HUU infants exposed to Option B+ PMTCT treatment regimens, with extended follow-up in the R33 phase for a total of for 4 years, and assessed for neurodevelopmental, mental health, hearing, growth outcomes and telomere length. An approach to survey older HEU/HUU (age 3-18) for neurodevelopmental and mental health outcomes and collect maternal medical, ART regimen and timing, and viral load data from medical records will be piloted in the R61 phase and expanded to 100 HIV clinics in the R33 phase. Selected neurodevelopmental/mental health screening and diagnostic tools to be used are based on open source availability, diagnostic or screening performance, cultural appropriateness, accessibility, and clinical relevance. In the national R33 survey, cost analysis will complement clinical data; and together, will be disseminated to stakeholders at a workshop to develop a framework for an integrated HEU screening program in public health settings. This proposal leverages extensive team experience in prior longitudinal MTCT cohorts, in national child and adolescent surveys, HEU recruitment, neurodevelopmental and mental health assessment, and medical record extraction and analysis at scale, to comprehensively understand burden, mechanism and outcomes in HEU. Engaging stakeholders has the potential to enhance HEU management programmatically based on findings.